Although breast cancer surgery and treatment have greatly improved in recent years, certain types of tumours are much more aggressive than others and therefore represent a greater risk to the patient. One such type of breast tumour is identified by the fact that it has high levels of a specific tumour marker called HER2. Therapies targeting HER2 have proven very successful, but there is a growing need to develop new therapies that might work from a different angle because many patients have become resistant to the existing drugs. In 2013, our lab were the first to publish that levels of HER2 can be regulated by a molecule called JAM-A. This suggested enormous potential in attacking HER2-dependent cancer signalling from the angle of targeting JAM-A rather than HER2 directly. Therefore we designed and synthesised a novel inhibitor of JAM-A signalling, KB3. In our preliminary tests, KB3 has shown promise in reducing HER2-dependent signalling in breast cancer cells. Therefore this grant proposal will use innovative patient-focussed models to rigorously test the potential of KB3 to reduce HER2-dependent breast cancer progression. Successful outcomes from the project would take us one step closer to having a completely new drug to target aggressive HER2-dependent breast cancers. The next step following on from this project would be the first testing of KB3 in humans. Overall we have strong evidence to suggest that our novel angle of using JAM-A as a target to get to HER2 could be a very valuable anti-cancer strategy for a large patient population.